Guidelines for treatment of atopic eczema (atopic dermatitis) part i

Guidelines for treatment of atopic eczema (atopicdermatitis) Part I J. Ring,†,‡,* A. Alomar,§ T. Bieber,– M. Deleuran,†† A. Fink-Wagner,‡‡ C. Gelmetti,§§ U. Gieler,––J. Lipozencic,††† T. Luger,‡‡‡ A.P. Oranje,§§§ T. Scha¨fer,––– T. Schwennesen,†††† S. Seidenari,‡‡‡‡D. Simon,§§§§ S. Sta¨nder,‡‡‡ G. Stingl,–––– S. Szalai,††††† J.C. Szepietowski,‡‡‡‡‡ A. Taı¨eb,§§§§§T. Werfel,––––– A. Wollenberg,†††††† U. Darsow,†,‡ For the European Dermatology Forum (EDF), and theEuropean Academy of Dermatology and Venereology (EADV), the European Task Force on Atopic Der-matitis (ETFAD), European Federation of Allergy (EFA), the European Society of Pediatric Dermatology(ESPD), and the Global Allergy and Asthma European Network (GA2LEN) †Department of Dermatology and Allergy Biederstein, Christine Ku¨hne-Center for Allergy Research and Education (CK-CARE),Technische Universita¨t Mu¨nchen, Munich, Germany‡Division of Environmental Dermatology and Allergy, Helmholtz Zentrum Mu¨nchen ⁄ TUM, ZAUM-Center for Allergy andEnvironment, Munich, Germany§Department of Dermatology, Hospital de Sant Pau, Universitat Autonoma Barcelona, Barcelona, Spain–Department of Dermatology and Allergy, University Bonn, Bonn, Germany††Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark‡‡EFA Project and Fundraising Officer, Konstanz, Germany§§Istituto di Scienze Dermatologiche, Universita` di Milano, Milano, Italy––Department of Psychosomatics and Psychotherapy, University of Gießen and Marburg GmbH, Gießen, Germany†††Department of Dermatology and Venereology, University Hospital Center Zagreb, Zagreb, Croatia‡‡‡Department of Dermatology, Competence Center Chronic Pruritus, University Hospital of Mu¨nster, Mu¨nster, Germany§§§Department of Pediatric Dermatology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands–––Institute for Social Medicine, University Lu¨beck, Lu¨beck, Germany††††Deutscher NEURODERMITIS Bund (DNB), Hamburg, Germany‡‡‡‡Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy§§§§Department of Dermatology, Universita¨tsklinik fu¨r Dermatologie, Bern, Switzerland––––Department of Dermatology, University of Vienna, Vienna, Austria†††††Department of Dermatology, Heim Pa´l Children’s Hospital, Budapest, Hungary‡‡‡‡‡Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland§§§§§Department of Dermatology and Pediatric Dermatology, Hoˆpital St Andre´, Bordeaux, France–––––Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany††††††Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany*Correspondence: J. Ring. E-mail: [email protected] The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors.
Anti-inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune-suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Stress-induced exacerbations may make psychosomatic counselling recommendable. ‘Eczema school’ educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies.
Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology A. Alomar has been speaker for Almirall, Astellas, Leti. T. Bieber has been advisor, speaker or investigator for ALK Abello´, Astellas, Bencard, Galderma, Glaxo SmithKline, Leo, Novartis, Stallergenes. U. Darsow has been speaker, investigator and ⁄ or been a member of advisory boards for Allergopharma, ALK Abello´, Bencard, GSK, Hermal, Novartis Pharma, Stallergenes, Stiefel. M. Deleuran has been a speaker, participated in clinical trials and ⁄ or been a member of advisory boards for Merck, Novartis, Astellas, Leo Pharma, NatImmune, Pergamum, Pierre Fabre and Janssen-Cilag.
A.-H. Fink-Wagner received honorarium from Pharmaxis and Chiesi during the last 3 years and was employed before that by Nycomed. J. Ring has been advisor, speaker or investigator for ALK Abello´, Allergopharma, Almirall ⁄ Hermal, Astellas, Bencard, Biogen-Idec, Galderma, Glaxo SmithKline, Leo, MSD, Novartis, Phadia, PLS Design, Stallergenes.
S. Sta¨nder was or is adviser, speaker and ⁄ or investigator for Aesca Pharma, Almirall ⁄ Hermal, Astellas Pharma, Beiersdorf AG, Birken, Essex Pharma, GSK, Pierre Fabre, Maruho, 3M Medica, Mundipharma, Novartis Pharma, Serentis, and Serono. Z. Szalai is investigator of clinical trials for Astellas, Novartis, Pfizer, Abbott, Pierre Fabre. A.
Taı¨eb has received consulting and clinical trial honoraria from Pierre Fabre, Astellas, Almirall ⁄ Hermal, Leo and Novartis.
T. Werfel has been advisor, speaker or investigator for ALK Abello´, Astellas and Novartis. A. Wollenberg has received research funding and lecture honoraria from, conducted clinical trials for, or is a paid consultant to Astellas, Basilea, GSK, Loreal, Merck, Novartis, MSD. Other authors declared no conflict of interest.
individuals) and subsequent increased susceptibility to Atopic eczema (AE; atopic dermatitis, eczema, ‘Neurodermitis’ in German speaking countries, endogenous eczema) is an inflamma- • Obvious strong psychosomatic influence with an imbal- tory, pruritic, chronic or chronically relapsing skin disease occur- ance in the autonomic nervous system with subsequent ring often in families with other atopic diseases (bronchial asthma increased production of mediators from various inflam- and ⁄ or allergic rhinoconjunctivis1).
matory cells (e.g. eosinophilic leucocytes).
Atopic eczema is one of the most common skin diseases which In the management of AE these various pathogenic reactions affects up to 20% of children and 1–3% of adults in most coun- have to be considered in an individual approach regarding the tries of the world.2 AE is often the first step in the development of abnormal reactivity patterns found in the individual patient other atopic diseases as rhinitis and ⁄ or asthma.
In the diagnoses of AE several criteria have been established.3,4 After establishing the diagnosis of AE, the severity of the disease There is no pathognomonic laboratory biomarker for diagnosis of has to be determined. The classical method is the ‘Scoring of AE, since the most typical feature, the elevation of total or Atopic Dermatitis’ (SCORAD) developed by the European Task allergen-specific IgE levels in serum or the detection of IgE- Force of Atopic Dermatitis (ETFAD). The SCORAD has been mediated sensitization in the skin test, is not present in all individ- modified by several authors.7 AE with a SCORAD higher than 40 uals suffering from AE; for this latter group the term ‘intrinsic’ is generally regarded as ‘severe’, whereas AE with a SCORAD (non-IgE-associated) AE has been introduced to distinguish it below 20 can be regarded as ‘mild’.
from ‘extrinsic’ (IgE-associated) forms of AE.5 This controversy in It has to be mentioned that the majority of cases with AE can terminology is going on until today1,6 and has practical implica- be regarded as ‘mild’ with 10–20% of patients suffering from tions with regard to specific avoidance strategies in the manage- severe eczematous skin lesions7; this percentage seems to be higher ment of this disease. In the aetiopathophysiology of AE several in the adult AE population. In the following, the most important aspects have to be taken into consideration: strategies in management and medication will be briefly discussed.
Apart from strong genetic influence (80% concordance in monozygous twins, 20% in heterozygous twins), there are charac- teristic features in pathophysiology as follows: The guideline committee decided that these guidelines should • Immune deviation towards Th2 in the initiation phase strictly concentrate on therapeutic regimens and omit longer chapters on clinical entity, diagnosis or pathophysiology of the • Deficient skin barrier function (‘dry’ skin) due to abnormal lipid metabolism and ⁄ or epidermal structural protein forma-tion (filaggrin mutation, protease inhibitor deficiency, etc.) • Abnormal microbial colonization with pathogenic organ- The existing evidence-based National guideline from Germany,8 isms such as Staphylococcus aureus or Malassezia furfur the HTA report9 as well as the position statement of the ETFAD10 (compared with Staphylococcus epidermidis in normal were compared and evaluated using the national standard Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology Guidelines for treatment of atopic eczena Appraisal of Guidelines Research and Evaluation (AGREE). The to the last internal review. The comments of the participating soci- committee decided that all the documents fulfilled enough criteria eties were forwarded to the chapter authors and considered during to be used as the base of the new evidence-based European Guidelines on Treatment of Atopic Eczema.
These guidelines will require updating approximately every Newer literature published after the German Guidelines8 and the 5 years. Based on new HTA reports the development of a S3 ETFAD Position Statement10 was searched using medline, This guideline has been prepared for physicians, especially derma- The evaluation of the literature focused on the efficacy of the ther- tologists, paediatricians, general practitioners and all specialists apeutic modality and was assessed with regard to the methodolog- taking care of patients suffering from AE. Also patients and rela- ical quality of the study according to the well-known criteria of tives should be able to get reliable information and evaluation with regard to evidence-based therapeutic modalities.
Based on the grade of evidence recommendations were classified Basic treatment of disturbed skin barrierfunction and emollient therapy (‘skin care’) The committee designated especially important areas as those requiring consensus. The consensus process consisted of a nominal Dry skin is one of the main symptoms of AE and part of the defini- group process and a DELPHI procedure. Consensus conferences tion. There is now scientific evidence in humans and mice of geneti- were held in Berlin October 2009, Cavtat May 2010, Munich July cally driven skin barrier anomalies that facilitate allergen 2010 and Goteborg October 2010, where the sections regarding penetration into the skin with an increased proneness to irritation consensus were discussed by the entire guidelines group following and subsequent cutaneous inflammation. Filaggrin deficiency is the best defined anomaly, which gives rise to a deficiency in small waterbinding molecules resulting from normal filaggrin catabolism.11 Besides that, a lack of stratum corneum intercellular lipids and an According to the EDF standard operation procedure all European inadequate ratio between compounds (cholesterol, essential fatty dermatological societies were invited to review the guidelines prior acids, ceramides) enhance trans-epidermal water loss leading to epi-dermal micro-fissuring. Barrier disruption leads to inflammation,and protease-antiprotease imbalance is a crucial intermediate step.12 The skin must be cleansed thoroughly, but gently and carefully to get rid of crusts and mechanically eliminate bacterial contaminants in the case of bacterial super-infection. Cleansers with or without antiseptics (the duration of action of antiseptics is very limited, thus mechanical cleansing is probably more important) in non- irritant and low allergen formulas available in various galenic forms (syndets, aqueous solutions) may be used. It is easier to perform this first stage of gentle cleansing of skin on the nappy mattress rather than directly in the bathtub in infants. A further cleansing followed by a rapid rinse is performed in the bath(27–30°C). The short duration of the bath (only 5 min) and theuse of bath oils (last 2 min of bathing) are aimed at avoiding Table 2 Classification of strength of recommendation epidermal dehydration. Topical emollients are preferentially applied directly after a bath or a shower following gentle drying when the skin is still slightly humid.
Adding sodium hypochlorite to the bath-water seems very important because of its bacterial count inhibiting activities. It may be advised to every treatment in AE. A recently published Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology study13 showed that children who took a bath using half a cup of bleach per full standard tub were relieved of their AE relateditching. The bleach apparently had very little odour. Salt baths Short-term (3–6 weeks) Several studies in children (e.g. 23,24 may be beneficial because of removing the dead keratolytic and one in a mixed children-adult population25 showed a variable, material.14 In heavily impetiginized or ichthyotic skin salt baths but consistent evidence of short-term steroid sparing effect in mild Long-term maintenance therapy Maintenance of stable disease The direct use of emollients on inflamed skin is poorly tolerated can be obtained with emollients used twice weekly or more fre- and it is better to treat the acute flare first. Emollients are the quently in a subset of patients, after an induction of remission with mainstay of maintenance therapy. Hydration of the skin is usu- topical corticosteroids. Several studies derived comparable results ally maintained by at least twice daily application of moisturizers for intermittent emollient therapy and time to relapse, using com- with a hydrophilic base, e.g. 5% urea. The use of barrier oint- parable study designs in adults and children.26,27 Regimens for ments, bath oil, shower gel, emulsions or micellar solutions basic ⁄ maintenance therapy are still awaiting validation based on enhancing the barrier effect is also recommended. The cost of systemic reviews and a Cochrane review (Oranje in prep.).
high-quality (low in contact allergens) emollient therapies oftenrestrict their use because such therapies are considered to be non-prescription drugs (except, e.g. Finland, where prescription Emollients should be prescribed in adequate amounts and these and reimbursement are usual) and the quantities required are should be used liberally and frequently, e.g. for emollient usually high (150–200 g per week in young children, up to cream ⁄ ointment a minimum of 250 g per week. Emollient bath 500 g in adults). A better molecular and biochemical knowledge oils and soap substitutes should also be used. In winter time more of the skin in AE should provide access to barrier improving lipid ingredients are preferable (3b, C).
topical agents. There is limited evidence-based proof for the use A regular use of emollient has a short- and long-term steroid sparing effect in mild to moderate AE. An induction of remissionwith topical corticosteroids is required first (2a, B).
Ingredients and possible risks of emollients The rapid progress in better molecular and biochemical knowl- Glycerol seems better tolerated (less smarting effect) than urea plus edge on the predisposing AE background should provide access to sodium chloride.16 Usually, the recommendation is to use emol- scientifically designed barrier improving topical agents, which lients immediately after bathing and soft pad drying. A small study indeed correspond to a major part of the aetiologic treatment of suggests that emollient applied alone without bathing have a the disease and are not limited to a mere symptomatic one (4, D).
longer duration as measured by capacitance.17 Propylene glycol is easily irritating in young children aged less than 2 years and should not be used in these young children.
There is evidence that the large preventive use of emollients con- Many patients are desperate when they hear from their physicians taining allergens such as peanut18 or oat19 may increase the risk of that AE is not ‘curable’. It is important to explain the difference skin sensitization and allergy. Only emollient preparations devoid between the genetic predisposition towards hypersensitive and dry of proteinaceous allergens and haptens (contact allergy) should be skin which cannot be ‘cured’ today and the acute eczematous skin used, especially in the most vulnerable age group before the age of lesions which can very well be treated and disappear. The identifi- cation of individual provocation factors is crucial in the manage- Sole use of emollients without sufficient topical anti-inflam- ment of AE and their avoidance allows longer phases of remission matory therapy involves a considerable risk for disseminated or total clearance of symptoms. In avoidance recommendations bacterial and viral infection, which is already increased in AE one has to distinguish between primary, secondary and tertiary prevention measures. Among provocation factors, specific andnon-specific elicitors have to be distinguished.
Certain moisturizers could improve skin barrier function in atopics and reduce skin susceptibility to irritants21. Lode´n et al.
Numerous factors and substances from the environment can irri- found in a comparative study between a glycerol-containing cream tate the sensitive skin of patients with AE and can elicit eczema and placebo an improvement over time in both groups indicating flares. They may be physical, like mechanic irritants (e.g. wool), the importance of emollient treatment in AE. Another study in chemical (acids, bleaches, solvents and water) or biological adult AE patients suggested an effect of coconut oil on Staphylo- (microbes) in nature. Information on unspecific irritants and their role in aggravating eczema is a crucial prerequisite for long-term Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology Guidelines for treatment of atopic eczena management of patients with AE. Here also the adequate skin care environment. In high altitude mountain climate pollen counts and hygiene procedures in cleansing and dressing have to be dis- are usually lower than in the average living areas.
cussed with the patient (see also Part II, ‘Educational Program,Eczema School’).
Animal epithelia Many patients are already aware that contact Negative effects of air pollutants upon the development and with animals is leading to a deterioration of the skin symptoms.
maintenance of AE, like tobacco smoke or volatile organic com- Although in former times avoidance of pets was a central feature pounds (VOCs) in indoor environments and traffic exhaust in in primary prevention recommendations for atopy, this has been the outdoor air have to be mentioned. There is evidence from modified as follows: cat epithelia exposure is regarded by most epidemiological trials that exposure to indoor chemicals, such as authors as a risk factor, so it should be avoided. There is no evi- formaldehyde, increases skin barrier disturbance;28 a mixture of dence that dogs increase the risk of AE in children. Once a patient volatile organic compounds has been shown to increase the is sensitized and allergic to a pet, avoidance is absolutely necessary.
intensity of atopy patch test (APT) reactions to aero-allergens in There is no evidence that pet keeping has a preventive effect in patients with AE.29 Exposure to traffic exhaust has been shown primary prevention of AE among normal population.
to be associated with an increased risk to develop AE in pre-school children.30,31 Dietary recommendations See chapter ‘Dietary intervention’.
Exposure to environmental tobacco smoke measured as urinary cotinin ⁄ creatinin ratio was associated with a significant elevated Clothing and textiles Smooth clothing and avoidance of irritat- risk to develop AE, which was especially pronounced in children ing fabrics and fibres is essential in the avoidance of primary skin irritation. Too occlusive clothing inducing heat sensations should Avoidance strategies regarding tobacco smoke as well as traffic be avoided. Early ear-piercing and use of nickel-releasing jewellery exhaust exposure in young children have been introduced in the has been found to be associated with a significantly elevated risk recent S3 guideline for primary prevention of atopy in of nickel contact allergy in young girls.42 Special recommenda- Germany.33,34 Certain food ingredients like alcohol, additives or tions have to be given in individual counselling programs with vasoactive amines may also trigger eczematous skin flares35; see regard to the choice of profession. There is common consensus that occupations with marked skin-damaging activity or contactwith strongly sensitizing substances should be avoided by patients Aeroallergens Aeroallergens have been shown to elicit eczema- tous skin lesions. In a rather high percentage of patients with AE There is some evidence that house dust mite avoidance strategies, the APT is positive (30–50%).36 Most common airborne allergens especially encasings, can reduce house dust mite and house dust eliciting eczema are derived from house dust mites of the species allergen content in indoor air and by that improve AE. The latter Dermatophagoides pteronyssinus and D. farinae. Also mold expo- is controversial, since some RCTs did not show this effect sure in damp indoor environment has been found to be associated There is evidence that house dust mite avoidance and high House dust mites are living in a complex eco-system consisting altitude climate may give benefit to patients suffering from AE of air humidity, temperature and organic material. They accom- pany humans and are most commonly present in dust from mat- There is a rationale for using protective clothes (eczema tresses or bedroom floors. Normal cleaning measures help only overalls), although good studies are missing (–, D).
little in decreasing house dust mite allergen present in the room.
In spring and summertime pollen exposure may exacerbate AE Encasings of mattresses and beddings protect humans from mites in the air-exposed skin areas; pollen avoidance measures can be contained in mattresses. There are also mite-proof pyjamas (‘eczema overalls’). There are some studies showing a clear-cut When classical patch tests are positive, relevant contact allergens benefit from house dust mite avoidance strategies in the improve- Rehabilitation programs in mite-free environments – like in alpine climate – have shown to lead to significant and long-lasting improvement of AE.38–40 Pollen in the outdoor air also can elicit flares of AE as has been shown in a nested case con- Among food allergens, cow’s milk, hen‘s egg, wheat, soy, tree nuts trol study in preschool children.41 Pollen avoidance is difficult and peanuts are most frequently responsible for eczema or under everyday conditions in most parts of Europe except exacerbation in infancy.44 In older children, adolescents and adults when air conditioning with pollen filters is used in the indoor pollen related food allergy should be taken into account.45,46 Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology Different types of clinical reactions to food have been described • The drop-out-rate in AE studies is particularly high in in patients with AE: Early reactions, such as urticaria, gastrointesti- nal or respiratory symptoms occur within 120 min after the • There is no convincing evidence that a milk- or egg-free administration of the allergens. Late phase responses, manifesting elimination diet is beneficial in general when unselected as eczematous lesions, occur after 2–48 h or some days. After oral groups of patients with AE were studied.
food challenge, about 50% of children with AE who reacted to • There is no evidence for a benefit in the use of elementary food showed both immediate and delayed reactions and 15% or few food restricted diets in patients with AE.
showed worsening of eczema only.47 The personal history is often A recently published systematic review identified a single pro- not helpful predicting late reactions to food with a positive predic- spective controlled study that supports the notion that a direct tive value of only 30% as opposed to 80% for immediate reac- elimination diet (in the study: egg exclusion) may be beneficial for the course of AE in sensitized patients with clinical symptoms Sensitizations to food can be identified by means of in vivo tests [skin prick tests (SPT), prick–prick tests] and in vitro tests (serumspecific IgE). In addition, patch tests proved to be useful forstudying delayed food-related skin responses. In vitro tests are valuable when SPT cannot be applied (e.g. dermographism or Patients with moderate to severe AE should observe a diet elimi- UV- and drug induced skin hypo-reactivity, eczema at the test nating those foods that elicitated clinical early or late reactions site, lack of compliance for SPT in infancy, etc.). Moreover, upon controlled oral provocation tests (2b, B).
in vitro specific IgE to food allergens give better quantitative datafor the grade of sensitization which helps to estimate the proba- bility of the risk of a clinical reaction (although precise decisionpoints are not available) and it offers the opportunity to test single recombinant allergens which may have a better diagnostic Effective topical therapy depends on three fundamental principles: specificity than testing with food extracts for some foods (e.g.
sufficient strength, sufficient dosage and correct application. Topi- omega-5-gliadin in wheat allergy, Gly m 4 in pollen-related soy cal treatment should always be applied on hydrated skin, especially when using ointments. The emollient should be applied first when Atopy patch tests are performed with self-made food material it is a cream, 15 min before the anti-inflammatory topical is applied to the back with large test chambers for 48–72 h. Food applied and when it is an ointment 15 min after. Patients with APT are not standardized for routine use.48 So far, APTs have acute, oozing and erosive lesions, and children in particular, some- demonstrated to improve the accuracy of skin testing in the diag- times do not tolerate standard topical application, and may first nosis of allergy to cow’s milk, egg, cereals, and peanuts in AE be treated with ‘wet wraps’ until the oozing stops. They are highly patients.49–55 Whereas immediate-type reactions are associated effective in acute eczema and improve tolerance. The use of wet- with SPT positivity, delayed ones are related to positive responses wrap dressings with diluted corticosteroids for up to 14 days to APTs. However, food challenge is not replaced by patch test- (usual is rather up to 3 days) is a safe crisis intervention treatment of severe and ⁄ or refractory AE with temporary systemic bioactivity The double-blind placebo-controlled food challenge is considered of the corticosteroids as the only reported serious side-effects.60,61 the gold standard for diagnosing food allergy.57 In AE, the evalua- Even without wet wraps, topical therapy is time consuming: tion of delayed reactions after 24 or 48 h by trained personal is patients should plan 30 min for one session. One well-conducted mandatory as stated by a recent position paper of the EAACI.58 treatment per day is usually sufficient; oozing eczema may require Challenge tests based on repeated exposure to food enable the a few days with higher treatment frequency.
assessment of delayed adverse responses.49,50,54,55 The major flaw By tradition, anti-inflammatory topical therapy has been is that they do not offer the opportunity to exclude placebo reac- administered to lesional skin only and has been stopped or tapered tions and ⁄ or coincidental influences of other trigger factors of AE down once visible lesions were cleared. This traditional, reactive during the prolonged challenge period.
approach has in the last years been challenged by the proactive Unfortunately, the effects of dietary interventions on the course treatment concept, which is defined as a combination of prede- of AE have been studied in a few controlled studies only so far.
fined, long-term, low dose, anti-inflammatory treatment appliedto previously affected areas of skin in combination with liberal use In a systematic review9 eight randomized, controlled studies of emollients on the entire body and a predefined appointment studying the effect of an elimination diet on existing AE were schedule for clinical control examinations.62 The first trial with identified and summarized in the following way: intermittent topical steroid use was published already in 1999.63 • Elimination diets are difficult to be performed even in a The proactive, usually twice weekly treatment regimen is started motivating atmosphere during a clinical study.
after all lesions have successfully been treated by an intensive, usu- Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology Guidelines for treatment of atopic eczena ally twice daily treatment approach in addition to ongoing emolli- pimecrolimus cream 1% combined with fluticasone were similar ent therapy for previously unaffected skin. Clinical trial data are available for a number of steroid products as well as for tacrolimus In a recent paper, it has been observed that glucocorticoids inhibited the double-stranded RNA (dsRNA)-induced release of Application amount of topical anti-inflammatory therapy thymic stromal lymphopoietin in the atopic cytokine milieu should follow the finger-tip unit (FTU) rule. A FTU is the amount at much lower concentrations than calcineurin inhibitors, of ointment expressed from a tube with a 5-mm diameter nozzle suggesting that they could be effective in the treatment of and measured from the distal skin-crease to the tip of the index AE when exogenous or endogenous dsRNA is involved in the finger (0.5 g); this is an adequate amount for application to two adult palm areas, which is approximately 2% of an adult body sur-face area.
Topical corticosteroids are important anti-inflammatory drugs to be used in AE, especially in the acute phase (–, D).
Topical glucocorticosteroids are a first-line anti-inflammatory Topical corticosteroids have a significant effect improving skin treatment, applied on inflammatory skin according to the lesions compared to placebo (1b, A).
needs (pruritus, sleeplessness, new flare). Numerous substances Topical corticosteroids with an improved risk-benefit ratio are are available in a variety of formulations. Evidence-based anti- inflammatory effects in AE were reported by different investiga- The efficacy of topical glucocorticosteroids (1b, A) can be tors.26,63,65 With mild disease activity, a small amount of topical increased by using wet wraps (1b, A).
corticosteroids twice to thrice weekly (monthly amounts in the Proactive ‘therapy’, e.g. twice weekly application in the long- mean range of 15 g in infants, 30 g in children and up to 60–90 g term follow-up may help to reduce relapses (1b, A).
in adolescents and adults), associated with a liberal use of emol-lients generally allows a good maintenance keeping SCORAD val- ues below 15–20. Such monthly amounts of even potent topical Both TCI, tacrolimus ointment and pimecrolimus cream, are steroids usually do not have adverse systemic or local effects.
licenced for topical eczema treatment. Various aspects of these Topical corticosteroids are grouped by potency, which should drugs have been reviewed in detail.73,74 The efficacy of both formu- be known to prescribers. In addition, there are different genera- lations has been demonstrated against placebo in clinical trials for tions of substances, which may differ in their risk-benefit ratio.
short-term75,76 and long-term use of these substances.77,78 In addi- Potent and very potent corticosteroids (Group III and IV) are tion, proactive tacrolimus ointment therapy has been shown to be more likely to cause depression of adrenal function than group I safe and effective for up to 1 year in reducing the number of flares (mild) and II (moderate strength) treatments, but their systemic and improving the quality of life in adult patients and children.79,80 effects will decrease more quickly due to more rapid restitution The anti-inflammatory potency of 0.1% tacrolimus ointment is of the skin barrier.66 Itch is the key symptom for evaluation of similar to a corticosteroid with intermediate activity,81 while the response to treatment, and tapering should not be initiated latter is clearly more active than 1.0% pimecrolimus cream.82 before the itch has disappeared. Dose tapering should be gradual Safety data of both TCI have been reported in many clinical tri- to avoid withdrawal rebound; tapering strategies consist of using als, demonstrating the safety of these drugs in daily routine use.
a less potent corticosteroid on a daily base, or keeping a more The most frequently observed side-effect is a transient warmth potent one while reducing the frequency of application (intermit- sensation or transient burning at the application site during the tent regimen). One well-conducted, correctly dosed treatment per first days of application.75,82 It starts about 5 min after each day is sufficient.67,68 The most constructive way to spare steroids application of the drug and may last up to 1 h, but intensity and and avoid steroid-related side-effects is not to spare them during duration typically decrease within 1 week to zero.83 Generalized acute flares, but through consequent baseline emollient skin care viral infections such as eczema herpeticum (EH) or eczema combined with early anti-inflammatory intervention to stabilize molluscatum (EM) have been observed during topical calcineurin the disease and prevent treatment-intensive flares.69 Usually one inhibitor treatment,84,85 but a high number of clinical trials failed daily application of topical steroids is sufficient.
to demonstrate an increased frequency or showed only a transient The special aspects and potential adverse effects of topical increase (reviewed in86–89). In contrast with corticosteroids, none corticosteroids in pregnancy are reviewed in a recent S3 guide- of the TCI induces skin atrophy.90,91 This favours their use over line.70 Twice weekly application of fluticasone significantly reduced topical corticosteroids in delicate body areas such as the eyelid the risk of relapses of eczema in a ‘proactive’ strategy.26,63,65 region, the perioral skin, the genital area, the axilla region or the The combination of topical corticosteroids with topical calci- inguinal fold and for topical long-term management. Two safety neurin inhibitors (TCI) does not seem to be useful. At least in pae- aspects of TCI regarding potentially increased malignancy rates are diatric patients with severe AE, the efficacy and safety profile of Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology discussed from time to time in the scientific community and the whom they are contraindicated. According to the latest knowledge, media – lymphoma risk and white skin cancer risk. Clinical and there is no scientific evidence of an increased risk for malignancy preclinical data do not indicate an increased risk of the induction due to a topical treatment with calcineurin inhibitors.94a of lymphoma over a period of 6 years92 or photocarcinogenicityfor TCI,93,94 but since the continuous oral administration of the calcineurin inhibitor cyclosporine is associated with an increased TCI are important anti-inflammatory drugs to be used in AE photocarcinogenicity risk in solid organ transplant patients, UV protection e.g. with sunscreens has been advised.81 The interpreta- TCI have a significant effect compared to placebo in short-term tion of the lymphoma risk should consider the fact, that a diagno- and long-term treatment of AE (1b, A).
sis of AD as such is associated with an increased risk for TCIs are especially indicated in problem areas (face, intertrig- lymphoma.92 A recent letter sent out on EMEA directive in 2012 nous sites, anogenital area; 1b, A).
from the manufacturing company of tacrolimus ointment to all Proactive therapy with twice weekly application of tacrolimus dermatologists in the EU could have induced again a feeling of ointment may reduce relapses (1b, A).
potential long-term risk of malignancies, but in fact it did not Effective sun protection should be recommended in patients communicate any new safety data, and indeed reassured physi- cians to follow the current label of tacrolimus ointment. Accordingto the latest knowledge, there is no scientific evidence of an increased risk for malignancy due to a topical treatment with calci- Itch is the most important clinical symptom in AE, with peculiar neurin inhibitors.94a The use of TCI under wet wraps or on erosive impact on emotional dimensions of perception as compared to lesions may increase systemic absorption.
other pruritic dermatoses like urticaria. Concerning pruritus The efficacy of long-term monotherapy with tacrolimus oint- accompanying AE, few studies investigate the antipruritic effect ment has been shown in children and adults.81,82 Less data are only. In most studies, pruritus is part of the total symptom score available for children under 2 years of age.95,96 Pimecrolimus using the EASI and SCORAD. For example, topical and systemic cream has been studied in infants and children in a combination corticosteroids, TCI, cyclosporine and UV-irradiation have signifi- regimen with topical corticosteroids,97,98 the latter being given if a cant influence on pruritus while only single studies specifically flare occurred. Both TCI are approved in the EU from 2 years of investigate the relief of pruritus intensity (Table 3).
age and above. Highquality long-term safety data have recentlybeen published from a 4-year tacrolimus and 26 weeks pimecroli-mus study.99,100 The cost effectiveness of proactive therapy with Table 3 Antipruritic therapies in AE. Recommendation for topi- topical tacrolimus has been demonstrated for moderate AE and is cal and systematical therapies based on clinical trials and expert even higher in severe AE in a recent study with adult patients,100a whereas the cost effectiveness of first-line treatment with TCI has not been shown conclusively. However, in children with AE, twice-weekly treatment with tacrolimus 0.03% ointment has been observed to reduce the number of flares and to prolong time spent free from flares with no additional cost in children with moderate factors: avoidance of toolong and hot bathing, AE, and may be cost-saving in those with moderate and severe In addition, the long-term, effective treatment of patients with AE may have a beneficial effect also on respiratory symptoms, and serum IgE.103 In adults, long-term treatment with 0.1% tacrolimus ointment appears to be at least as effective as a corticosteroid regi- men for the trunk and extremities, and more effective in the face Pimecrolimus, t*Ultraviolet light (NB-UVB) and neck area. Both topical tacrolimus and corticosteroids increase skin recall activity, and decrease serum IgE in patients with good treatment response. Taken together, these results suggest that skin inflammation in AE should be treated effectively, which could lead to an improvement in the Th1 ⁄ Th2 balance in the skin, and to long-term improvement in the severity of the AE.103,104 These drugs are recommended for use as second-line therapy for the short-term and non-continuous treatment of AE in patients AE, atopic eczema; t, topically; o, orally.
who do not respond adequately to topical corticosteroids or in *As proven by randomized, controlled trials.
Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology Guidelines for treatment of atopic eczena Antipruritic therapy in AE is multidimensional treating the study proved that Narrowband-UVB was more effective than symptom itself, the contributing factors such as dry skin, inflam- mation and the related scratch lesions. Therefore, several generalmeasures can be recommended (see ‘Basic treatment’). Based on expert opinion, short-term relief of pruritus can be achieved by There is evidence that UV-therapy can be used in AE to relieve topicals containing urea, camphor or menthol preparations as well pruritus. Narrow band UVB seems to be most preferable (2b, B).
as wet, cooling or fat-moist wrappings,61 wrappings with black tea,short and lukewarm showers. Unspecific physical modalities are Cyclosporine A See ‘Systemic Immunosuppression’ (Part II).
described to be beneficial like acupuncture,105 and cutaneous fieldstimulation.106 Intravenous Immunoglobulin therapy See ‘Systemic Immuno-suppression’.
Anti-inflammatory therapies acting on pruritus Mycophenolat mofetil See ‘Systemic Immunosuppression’.
Glucocorticosteroids Several studies describe the anti-inflam-matory effect of topical corticosteroids in AE, in which pruritus was one parameter among others such as erythema, induration,scaling and excoriation (see chapter Topical Anti-inflammatory Topical anaesthetics Local anaesthetics such as benzocaine, lido- Therapy). In sum, these studies suggest that topical corticosteroids caine, polidocanol as well as a mixture of prilocaine and lidocaine have a rapid antipruritic effect and can also be used in ‘proactive’ are widely used as short-term effective topical antipruritics. In therapy.107 No study focuses solely on the onset, mechanisms and experimental studies, the antipruritic effect of local anaesthetics duration of the pruritus relief in AE. However, it seems likely that was demonstrated in AE118 but controlled clinical trials investigat- the anti-inflammatory effect of glucocorticosteroids is responsible ing the antipruritic effects of local anaesthetics in AE are pending.
to partly abolish pruritus.108 This also holds true for systemic Case series described the efficacy of a combination of polidocanol glucocorticosteroids, for which no specific studies on an anti-itch and 5% urea.119 In children with AE, the combination showed a pruritus improvement of 30% in comparison with an emollient.120None of these substances is licenced for AE in Europe.
There is evidence that topical corticosteroids can be used in the initial phase of AE exacerbation to control pruritus (1b, A).
Although there is evidence that short-term application of topicallocal anaesthetics may reduce itch sensation in AE (4, C), routine Interferon (IFN) gamma Interferon gamma appears to have a clinical use in AE cannot be recommended as an adjuvant antipru- beneficial effect on pruritus in AE.109 In a double-blind study, pru- ritus was reduced by 50% even 1–2 years after long-term treat-ment with recombinant human interferon gamma.110 Cannabinoid receptor agonist Topical cannabinoid receptor ag-onists have been described to exhibit antipruritic and analgesic properties. Experimentally induced pain, itch and erythema could There is evidence that systemic IFN gamma influences AE itch, be reduced by application of a topical cannabinoid agonist.121 One however, therapeutical use was not further investigated following cosmetic product containing the cannabinoid agonist N-palmitoy- lethanolamin was used in a multicentric, large cohort, open labelstudy as adjuvant treatment in AE.25 2456 patients including over inhibitors Topical calcineurin inhibitors relieve 900 children applied the cream twice daily. Pruritus and the need significantly pruritus in AE. Itch is completely relieved after the to use corticosteroids were reduced up to 60%.
first days of treatment in adults and children. Studies report ofrelief even 3 days of topical application of tacrolimus111,112 and There is preliminary evidence that topical N-palmitoylethanolaminmay be effective as an adjuvant antipruritic therapy in AE, but fur- ther trials are needed before an evidence based recommendation There is evidence that TCI can be used in AE until clearance of Capsaicin Capsaicin, a naturally occurring alkaloid and the UV therapy UV irradiation relieves pruritus in AE demonstrated principal pungent of hot chilli peppers, has been advocated to be in a study that compared UVB to placebo treatment.115 Also a antipruritic in various dermatoses. Repeated topical application of Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology capsaicin releases and prevents specifically the reaccumulation of randomized studies in AE. A dosage of 10 and 20 mg each once neuropeptides in unmyelinated, polymodal C-type cutaneous per day showed significant relief of pruritus in three studies.131–133 nerves. Capsaicin exerts its functions via binding to a capsaicin- In open label trials and one double-blind, placebo-controlled specific receptor, i.e. the transient receptor potential channel study trial, the only orally active mu-opioid antagonist naltrexone vanilloid (TRPV1) which is located on free nerve endings.
25–150 mg per day showed considerable antipruritic effects.134,135 Concerning AE, experimental studies122 and case series123 report None of these substances is currently licenced for treatment of on clear itch reduction. No controlled study was performed as of Although there is evidence that opioid receptor antagonists nal- There is preliminary evidence that capsaicin is useful in the treat- trexone and nalmefene may reduce AE itch (1b, A), there is insuf- ment of AE itch but further trials are needed before an evidence ficient data to recommend routine use of these substances in AE.
based recommendation can be given (4, B).
Topical doxepin Five percent doxepin cream exhibited antipru- Selective serotonin reuptake inhibitors The antipruritic effect ritic effects in controlled studies in AE.124 However, topical doxe- of the selective serotonin reuptake inhibitor paroxetin and fluvox- pin therapy is not licenced and not used in any European country amin was investigated in an open label trial in dermatological due to an increased risk of contact allergy, especially when the patients. Single patients with pruritus due to AE were included which responded with considerable reduction of pruritus. In thesepatients, the pruritus was reduced about half of intensity (maximal antipruritic effect score, 45.0 ± 7.1%).136 At the moment there is not enough RCT evidence to support theuse of doxepin in the treatment of AE itch (2b, B).
At the moment there is not enough RCT evidence to support the Topical mast cell stabilizers Mast cell mediators such as use of selective serotonin reuptake inhibitors paroxetine and flu- tryptase and histamine contribute to induction of pruritus in AE.
voxamine in the treatment of AE itch (4, C).
Accordingly, the application of mast cell degranulation inhibitorsor stabilizers seems reasonable. However, in a multicenter, double- blind, placebo-controlled trial applying 3% hydrogel formulation Antihistamines have been used for decades, in an attempt to relieve of tiacrilast (mast cell inhibitor) against vehicle in atopic dermati- pruritus in patients with AE. However, only a few randomized tis, there was no significant improvement of pruritus.125 In controlled trials have been conducted and they have in the majority another study, pruritus in children with AE responded to topical shown only a weak or no effect in decreasing pruritus.137–142 sodium cromoglycate,126 which was proven by a recent placebo- The first generation of sedative antihistamines, such as hydroxy- zine, clemastine fumarate and dimetinden maleate, may allow abetter sleep pattern in acute situations with exacerbations of eczema (evidence level D). Concerning the newer non-sedating antihista- At the moment there is not enough RCT evidence to support the mines, single studies using loratadine, ceterizine or fexofenadine use of mast cell stabilizers in the treatment of AE itch (2b, B).
demonstrated no or only a weak relief of pruritus in AE143–145. Asignificant, but clinically small, antipruritic effect of fexofenadine Leukotriene receptor antagonists Preliminary studies showed 60 mg twice daily has been described.108 An effect on itch of a high reduction of pruritus in patients with AE during treatment with dosage of 20–40 mg ceterizine daily has been observed, but this the leukotriene receptor antagonists zafirlukast and zileuton.128–130 effect was primarily attributed to sedation.144 However, due to a high rate of side-effects the substances were not Diepgen et al.146 reported in infants with severe AE acorticoste- developed to regular therapies of AE.
roid sparing effect of ceterizine and judged this as an indirect mea-sure for the efficacy of ceterizine on pruritus. Murata et al.147 compared in patients with pruritic diseases (including eczema At the moment there is not enough RCT evidence to support the cases) effects of sedating and non-sedating antihistamines: similar safe use of leukotriene receptor antagonists in the treatment of AE effects on itch intensity were seen, but only non-sedating antihista- mines reduced significantly the impairment in work productivityand daily activity.
Opioid receptor antagonists naltrexone and nalmefene The In general, antihistamines are safe to use, also for a long period mu-opioid receptor antagonist nalmefene was applied in controlled, of time,148 and the major advantage seems to be relief of the symp- Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology Guidelines for treatment of atopic eczena toms of co-morbidities such as allergic asthma, rhino-conjunctivi- The use of silver-coated textiles and silk fabric with the durable tis, urticarial dermographism and urticaria. Topical antihistamines antimicrobial finish AEGIS ADM 5772 ⁄ S can reduce S. aureus col- have no effect on itch beyond that of their cooling vehicles.
onization and eczema severity.164–166 These newer options are still under investigation. Of note, there is some concern about the There are limited data for the antipruritic effect of antihista- safety of silver-coated textiles in infants and toddlers.
mines (H1-antagonists) in AE, and the effect of both first and sec- Secondary infections with yeasts, dermatophytes or streptococ- ond generation antihistamines on pruritus, in patients suffering cal infections have also been implicated as trigger factors in AE.167 Intense erythema in skin folds of children with a flare of AE maywarrant a search for streptococcal skin infection. In general, signs of secondary infections should be treated if present. Antimycotics There is not enough evidence to support the general use of both are proposed for the treatment of ‘head and neck’ variant of AE, first and second generation antihistamines (H1-antagonists) for often associated with Malassezia sympodialis superinfection treatment of pruritus in AE (1b, A).
(recently reviewed by Darabi et al.168 Systemic ketoconazole169and topical ciclopiroxolamine170 have been shown to improve eczema significantly within 4 weeks in placebo-controlled trials in A number of defects in innate cutaneous immunology may patients with ‘head-neck-shoulder dermatitis’. Instead of keto- explain the high rate of cutaneous colonization with Staphylococ- conazol, other imidazole derivates (fluconazol or itraconazol) are cus aureus (up to 90% in moderate to severe eczema) in proposed nowadays due to a better benefit : side effect ratio.
AE.149,150 There is evidence for an association of S. aureus-derived Viral infections are occurring more frequently in AE patients exotoxins including superantigens and pore forming haemolysins than in normal individuals, with a tendency to disseminated, with disease exacerbation,151–153 reviewed by De Benedetto widespread disease and named after the causative virus as eczema et al.149 and Niebuhr and Werfel150 supporting early observations molluscatum, eczema vaccinatum or EH.20 EH has been described that the density of S. aureus colonization in AE is significantly following corticosteroid and calcineurin inhibitor therapy, but correlated with clinical severity,154 and that patients with severe recent data indicate that patients with severe, untreated AE, a high AE may improve (but not be cured) by antistaphylococcal treat- total serum-IgE and early onset of AE are at risk for EH, whereas ment.155 In severe exacerbations systemic antibiotic treatment pretreatment with topical corticosteroids does not imply a risk.171 The mainstay of EH therapy is prompt systemic antiviral chemo- In general, improving eczema with anti-inflammatory regimen therapy with i.v. aciclovir, but a number of alternative treatment (i.e. TCS, TCI and UV) decreases staphyloccocal colonization. This led to the clinical concept that patients with high numbers of colo-nizing S. aureus can benefit from combination treatment with cor- ticosteroids and antimicrobial treatment, in most cases using Oral antibiotics have no benefit on the skin condition in AE as topical antiseptics like triclosan, chlorhexidine or cristal violet long as skin lesions are not obviously superinfected (1b, A).
0.3%.156,157 In addition, a combination of natriumhypochlorite in A short-term treatment with systemic antibiotics may be benefi- baths with antibiotics has recently been published to have minor cial if the skin is obviously superinfected with bacteria (2b, B).
to moderate effects on eczema in children with AE.13 However, There is evidence from open observational studies only that formal evidence on beneficial effects of topical antiseptics coming antiseptic substances are beneficial for the treatment of AE (4, C).
from prospective controlled studies is still not available. A recent An antimycotic therapy may be efficient in AE patients suffering Cochrane review did not find any benefit for antibacterial soaps from the ‘head and neck’ variant (2b, B).
(1 trial, 50 participants), or antibacterial bath additives (2 trials, 41 Topical glucocorticosteroids or calcineurin inhibitors reduce the participants), or topical antibiotics ⁄ antiseptics (4 studies, 95 colonization rate of Staphylococcus aureus in AE (4, C).
Antiseptic textiles have a moderate clinical effect on AE (2b, B).
Apart from specific indications such as overt secondary infection The long-term application of topical antibiotics is not recom- or presence of beta-hemolytic streptococci159,160 or from visual mend due to the risk of increasing resistances and sensitizations (the superinfections of the skin with S. aureus, treatment of eczema latter being relevant for a subgroup of topical antibiotics only; –, D).
with antibiotics had no effect in regards to clinical improvement EH should be treated without delay using systemic antiviral and sparing of steroids161 and should therefore not be performed.
therapy, such as systemic aciclovir (4, D).
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